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Scientists document complex genomic events leading to the birth of new genes

A team of scientists led by Peer Bork, Ph.D., Senior Bioinformatics Scientist at the European Molecular Biology Laboratory, report today in the journal Genome Research that they have identified a new primate-specific gene family that spans about 10% of human chromosome 2. Comprised of eight family members, the RGP gene cluster may help to explain what sets apart humans and other primates from the rest of the animal kingdom.

Human chromosome 2 has always intrigued primate biologists; it formed from the fusion of two mid-sized ape chromosomes and is the only cytogenetic distinction separating humans from apes. At the molecular level, however, the differences among the species are much more complex.

Bork's team systematically searched the complete genomic sequences from a broad range of taxa (mouse, rat, roundworm, fruit fly, mosquito, and pufferfish) for single-copy genes that had evolved more than one copy in humans. "Gene duplication is known to play a leading role in evolution for the creation of new genes," explained Francesca Ciccarelli, Ph.D., lead author on the study. The key to this, however, is that the duplicated copies of genes very quickly evolve functions that are significantly different than those of their progenitors.

Natural selection acts on gene duplications, most often by deleting them from the gene pool or by degrading them into non-functional pseudogenes. This is because fully functional duplicated genes, in combination with the corresponding parent gene, produce abnormally abundant quantities of transcripts. This overexpression often alters the fragile molecular balance of gene products on a cellular level, ultimately resulting in deleterious phenotypic consequences. If these duplicated genes acquire new functions, however, they may confer a selective advantage to an organism, leading to the rise of lineage-specific genes over evolutionary time.

Bork's team identified a total of 22 genes with more than one co py in humans but only a single copy in all other species tested. They then turned their attention to the gene that exhibited the most dramatic of these duplications: RanBP2. RanBP2 is the largest protein found at the nuclear pore complex, helping to regulate nucleic acid and protein traffic in and out of the nucleus. The corresponding gene is present in all sequenced animal genomes but not in other eukaryotes, such as plants or fungi.

The new gene family characterized by Dr. Bork and his colleagues was largely derived from RanPB2, but it had also acquired a domain from the neighboring GCC2 gene, whose protein product contains a GRIP domain that localizes intracellularly to the trans-Golgi network. The new gene family, spanning approximately 10% of human chromosome 2, was named RGP (for RanBP2-like, GRIP domain-containing proteins).

By analyzing the gene order around the RanBP2 and GCC2 genes, Bork's team was able to reconstruct the genomic rearrangements leading to the formation of the ancestral RGP locus. These events included a combination of duplication, inversion, partial deletion, and domain acquisition, and this was followed by a series of duplications that gave rise to each RGP family member. A total of eight RGP-family genes were identified, all of which are believed to be fully functional.

To demonstrate that RGP-family genes have functions that are significantly divergent from those of RanBP2, Bork and his co-workers examined the subcellular localization of one of the RGP-family isoforms. In contrast to RanBP2, which is found exclusively at the nuclear envelope, this RGP-family protein was detected in discrete cytoplasmic locations, thereby confirming its functional divergence from RanBP2.

Identifying and characterizing genes that are responsible for primate or human distinctiveness has been a major challenge to scientists. However, this work by Bork and his colleagues should further enable studies focused on the molecular b asis for species specificity. "A thorough functional characterization of the other 21 new genes we've identified in this study would reveal the functionally most relevant areas for primate evolution," Bork says.


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Source:Cold Spring Harbor Laboratory


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